EGFR ligand shifts the role of EGFR from oncogene to tumour suppressor in EGFR-amplified glioblastoma by suppressing invasion through BIN3 upregulation

Gao Guo, Ke Gong, Nicole Beckley, Yue Zhang, Xiaoyao Yang, Rati Chkheidze, Kimmo J. Hatanpaa, Tomas Garzon-Muvdi, Prasad Koduru, Arifa Nayab, Jennifer Jenks, Adwait Amod Sathe, Yan Liu, Chao Xing, Shwu Yuan Wu, Cheng Ming Chiang, Bipasha Mukherjee, Sandeep Burma, Bryan Wohlfeld, Toral PatelBruce Mickey, Kalil Abdullah, Michael Youssef, Edward Pan, David E. Gerber, Shulan Tian, Jann N. Sarkaria, Samuel K. McBrayer, Dawen Zhao, Amyn A. Habib

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

The epidermal growth factor receptor (EGFR) is a prime oncogene that is frequently amplified in glioblastomas. Here we demonstrate a new tumour-suppressive function of EGFR in EGFR-amplified glioblastomas regulated by EGFR ligands. Constitutive EGFR signalling promotes invasion via activation of a TAB1–TAK1–NF-κB–EMP1 pathway, resulting in large tumours and decreased survival in orthotopic models. Ligand-activated EGFR promotes proliferation and surprisingly suppresses invasion by upregulating BIN3, which inhibits a DOCK7-regulated Rho GTPase pathway, resulting in small hyperproliferating non-invasive tumours and improved survival. Data from The Cancer Genome Atlas reveal that in EGFR-amplified glioblastomas, a low level of EGFR ligands confers a worse prognosis, whereas a high level of EGFR ligands confers an improved prognosis. Thus, increased EGFR ligand levels shift the role of EGFR from oncogene to tumour suppressor in EGFR-amplified glioblastomas by suppressing invasion. The tumour-suppressive function of EGFR can be activated therapeutically using tofacitinib, which suppresses invasion by increasing EGFR ligand levels and upregulating BIN3.

Original languageEnglish (US)
Pages (from-to)1291-1305
Number of pages15
JournalNature Cell Biology
Volume24
Issue number8
DOIs
StatePublished - Aug 2022

ASJC Scopus subject areas

  • Cell Biology

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